CN102686279A - Carrier composition - Google Patents

Carrier composition Download PDF

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CN102686279A
CN102686279A CN201080058887XA CN201080058887A CN102686279A CN 102686279 A CN102686279 A CN 102686279A CN 201080058887X A CN201080058887X A CN 201080058887XA CN 201080058887 A CN201080058887 A CN 201080058887A CN 102686279 A CN102686279 A CN 102686279A
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carrier compositions
preparation
bioactive compound
phenolic group
phosphate ester
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CN102686279B (en
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保罗·大卫·加文
马哈茂德·埃尔-塔米米
杰里米·詹姆斯·科特雷尔
贾钦托·加埃塔诺
尼古拉斯·约翰·肯尼迪
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Phosphagenics Ltd
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Phosphagenics Ltd
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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Abstract

A carrier composition of the present invention comprises a phosphate compound of an electron transfer agent and a relatively high concentration of a polar protic solvent. A biologically active compound may be formulated with a carrier composition of the present invention to provide a formulation.

Description

Carrier compositions
Technical field
The present invention relates to be used for the carrier compositions of delivery of bioactive compounds.
Background technology
Quote or discuss in this description under the situation of file, decree or clause of knowledge, this quote or discuss and be not equal to file, decree or the clause of approving this knowledge or its combination in any when priority date be publicly available, the public is known, the part of common sense; Or it is known with to attempt to solve the related any problem of this description relevant.
Medicine is sent and is meant that the drug administration chemical compound is to realize the method or the process of therapeutic effect in humans and animals.
Bioavailability, safety, persistent period, onset or the release of developing drugs delivery technique to improve medical compounds.
When the developing drugs delivery technique, the problem that possibly run into comprise drug delivery system and medical compounds the compatibility, keep enough and effectively persistent period, potential side effect and the convenience and the compliance that satisfy the patient.Therefore, many medicine delivery techniques do not reach the improvement and the demand of expectation.
Therefore, the alternative drugs delivery system that still needs effective delivering drugs.
Summary of the invention
Find unexpectedly, comprise the phosphate cpd of electron transfer agent and the carrier compositions of the polar protic property solvent of relative high concentration and can improve sending of bioactive compound.
According to a first aspect of the invention; A kind of phosphate cpd that comprises electron transfer agent of delivery of bioactive compounds and carrier compositions of polar protic property solvent of being used for is provided, and wherein said polar protic property solvent strength is higher than the 50%w/w of said carrier compositions total concentration.
The phosphate cpd and the purposes of polar protic property solvent in making carrier compositions of electron transfer agent also are provided.
A kind of method for preparing carrier compositions also is provided, and it comprises the phosphate cpd of electron transfer agent and polar protic property solvent combinations until the step that reaches complete homogenize.
Polar protic property solvent strength preferably at about 60%w/w to about 90%w/w, extremely about 85%, the about 70%w/w extremely in the scope of about 80%w/w most preferably of about 65%w/w more preferably.In some cases, the scope that is fit to can be about 50%w/w to about 60%w/w, about 60%w/w is about 70%w/w or about 80%w/w about 90%w/w extremely extremely.
In one embodiment, said polar protic property solvent is an acyclic alcohol.Preferred C 2-C 3Acyclic alcohol, most preferred ethanol and propanol.
Said electron transfer agent can be antioxidant or its derivative compound.In a preferred embodiment, said electron transfer agent is a hydroxychroman, and preferred tocol (tocol) is like tocopherol or tocotrienol.
The phosphate cpd of tocopherol can be selected from list-(fertility phenolic group) phosphate ester, list-(fertility phenolic group) phosphate ester list sodium salt, list-(fertility phenolic group) phosphate ester monopotassium salt, list-(fertility phenolic group) organic phosphate disodium salt, list-(fertility phenolic group) phosphate ester di-potassium, two-(fertility phenolic group) phosphate ester, two-(fertility phenolic group) phosphate ester list sodium salt, two-(fertility phenolic group) phosphate ester monopotassium salt or its mixture.
When carrier compositions comprises the mixture of list-(fertility phenolic group) phosphate ester and two-(fertility phenolic group) phosphate ester, its ratio preferably at least 2: 1, more preferably about 4: 1 to about 1: 4 scope, most preferably at about 6: 4 to about 8: 2 scope.In preferred embodiments, said ratio is about 6: 4 or about 8: 2.
Carrier compositions comprises the phosphate cpd of the electron transfer agent of following amount: preferably at about 0.01%w/w of carrier compositions total concentration to about 20%w/w, more preferably about 0.01%w/w is to about 10%w/w, extremely about 5%w/w or about 0.01%w/w extremely in the scope of about 1%w/w of about 0.01%w/w most preferably.In one embodiment, said carrier compositions comprises the phosphate cpd of the electron transfer agent of following amount: in the scope of about 0.01%w/w to 2%w/w, and preferably about 0.05%w/w, about 0.1%w/w or about 1%w/w.In another embodiment, can use about 5%w/w to about 10%w/w or the about 10%w/w scope of about 15%w/w extremely.
In second aspect of the present invention, the preparation that comprises said carrier compositions and bioactive compound is provided.
The method for preparing said preparation also is provided, has comprised the step of bioactive compound being added to said carrier compositions.
In one embodiment, said bioactive compound is lipophilic, its logP value about 1 to about 5 scope.Preferably, this bioactive compound also has low relatively molecular weight and low relatively fusing point.
Bioactive compound can exist with the amount up to about 30%w/w of carrier compositions total concentration.
In the third aspect of the invention, provide said carrier compositions to be used to improve the purposes of sending of the bioactive compound of preparing with said carrier compositions.
Also provide said carrier compositions to be used to change the purposes of the A.D.M.E. characteristic of bioactive compound.
Also provide said carrier compositions to be used for improving the purposes of bioactive compound in the bioavailability of object.
In fourth aspect of the present invention, a kind of method of disease of treatment target is provided, comprise the bioactive compound that is applied in the effective dose in the said carrier compositions.Said disease comprises those diseases that the available bioactive compound of preparing with carrier compositions is treated.
Detailed Description Of The Invention
Carrier compositions of the present invention comprises the phosphate cpd of electron transfer agent and the polar protic property solvent of relative high concentration.Can bioactive compound be prepared so that preparation to be provided with carrier compositions of the present invention.
In this description, only if context has requirement in addition, word " comprises " and " containing " means " comprising ", and promptly when the present invention being described or is defined as when comprising characteristic specified, the different embodiments of identical invention can also comprise additional features.
The phosphate cpd of electron transfer agent
Term " electron transfer agent " but mean the chemical compound of phosphorylation, and said chemical compound can be accepted electronics and produces metastable molecular radical or can accept two electronics and make chemical compound can participate in reversible oxidation-reduction system when the non-phosphorylating form.The instance of electron transfer agent comprises antioxidant and derivant thereof.
Term " antioxidant " means the molecule that can slow down or prevent other molecular oxidations.Oxidation is a kind of with the chemical reaction of electronics from the substance transfer to the oxidant.Oxidation reaction can produce the free radical of the chain reaction that starts the infringement cell.Antioxidant stops these chain reactions through removing free radical intermediate, and suppresses other oxidation reactions through autoxidation.Therefore, antioxidant usually is a Reducing agent.
Antioxidant is divided into two big types substantially, and this depends on their whether water soluble (hydrophilic) or oils and fatss (hydrophobic).Ascorbic acid (vitamin C) is the instance of water soluble antioxidant.Carotene, tocopherol (vitamin E), retinol (vitamin A), pantothenylol (the reduction form of ubiquinone) and calciferol (vitamin D) are the instances of fat-soluble antioxidant.
Carotene (carotene) is oxygen-free carotenoid.Carotenoid replaced by hydroxyl based on carotene one of them or more a plurality of hydrogen atom and/or some hydrogen atoms to being replaced by oxygen atom.Term " hydroxy kind carotene " is meant with the substituted carotene of one or more hydroxyl.Cryptoxanthine (cryptoxanthin) is the instance of hydroxy kind carotene: it and beta-carotene are closely related, have just increased hydroxyl.
Vitamin E exists with eight kinds of different forms, i.e. four kinds of tocopherols and four kinds of tocotrienol.Form of ownership is a characteristic with the chromane ring all, this chromane endless belt have can provide hydrogen atom with the reduction free radical hydroxyl with make it penetrate into biomembranous hydrophobic side chain.These derivants of vitamin E can classify as " hydroxychroman " (" hydroxy chromans ").Tocopherol and tocotrienol all exist α, β, γ and δ form, and this is by the quantity and the determining positions of methyl on the chromane ring.Be different from similar tocopherol, there are three two keys in tocotrienol in hydrophobic side chain.Vitamin E multi-form suc as formula shown in (I):
Figure BDA00001798709900041
Figure BDA00001798709900051
Retinol (retinol) belongs to the chemical compound family that is called as retinoid (retinoid).Three generations's retinoid is arranged.First generation retinoid comprises retinol, retinal, retinoic acid (tretinoin) (tretinoin, all-trans-retinoic acid), Accutane and A Li retinoic acid (alitretinoin).Second filial generation retinoid comprises etretinate (etretinate) and its metabolite Ah Qu Ting (acitretin).Third generation retinoid comprises tazarotene, bexarotene and adapalene (adapalene).
Pantothenylol is the benzo chinol and is ubiquinone (ubiquinone 10) the reduction form.
Calciferol (vitamin D) has several kinds of forms.Two kinds of principal modes are vitamin D 2(for example ergocalciferol) and vitamin D 3(for example calcitriol, cholecalciferol).Other forms comprise vitamin D 1(molecular complex of ergocalciferol and lumisterol (lumisterol), 1: 1), vitamin D 4(22-dihydro ergocalciferol) and vitamin D 5(the paddy calciferol is made by 7-dehydrogenation sitosterol).
Any antioxidant or derivatives thereof described herein is suitable for the present invention.Preferred anti-oxidants and derivant thereof are selected from carotenoid, hydroxychroman, carotenoid, retinoid, benzo chinol and calitriol.Preferred hydroxychroman.Most preferably any type of tocol (for example tocopherol).
Term " phosphate cpd " refers to the chemical compound of phosphorylation, at the oxygen atom (coming from hydroxyl usually) and the phosphate (PO of chemical compound 4) phosphorus atoms between form covalent bond: among this paper, said chemical compound is an electron transfer agent.
Phosphate cpd can be phosphate monoester, di-phosphate ester, phosphotriester, pyrophosphoric acid monoesters, pyrophosphate diesters or its salt or derivant or its mixture.Diester can comprise identical electron transfer agent or different electron transfer agents with three esters.
" salt " comprises slaine, like alkali metal salt or alkali salt, and for example sodium salt, magnesium salt, potassium salt and calcium salt.Particular certain cancers and potassium salt.
" derivant " comprises that one or more phosphoric acid proton is substituted basic substituted phosphate cpd.Some limiting examples of derivant comprise the sugar derivatives that replaces the phosphoric acid proton with the phosphatidyl derivant of amino-alkyl group replacement phosphoric acid proton, with sugar (like glucose).
Term " amino-alkyl group " is meant and comprises amino (NH 2) and the group of alkyl.Term " alkyl " is meant straight chain, side chain or the cyclic hydrocarbon group with 1 to 8 carbon atom.Instance comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, cyclohexyl, heptyl and octyl group.Derivative of phosphatidylcholine most preferably.
For example; When said electron transfer agent was tocopherol, the phosphate cpd of tocopherol can be selected from list-(fertility phenolic group) phosphate ester, list-(fertility phenolic group) phosphate ester list sodium salt, list-(fertility phenolic group) phosphate ester monopotassium salt, list-(fertility phenolic group) organic phosphate disodium salt, list-(fertility phenolic group) phosphate ester di-potassium, two-(fertility phenolic group) phosphate ester, two-(fertility phenolic group) phosphate ester list sodium salt, two-(fertility phenolic group) phosphate ester monopotassium salt or its mixture.These phosphate cpds can be derived from α, β, γ or δ form or its combination of tocopherol.
When carrier compositions comprises the mixture of list-phosphate ester and two-phosphate ester (for example list-(fertility phenolic group) phosphate ester and two-(fertility phenolic group) phosphate ester); Its ratio preferably at least 2: 1; More preferably about 4: 1 to about 1: 4 scope, most preferably at about 6: 4 to about 8: 2 scope.Ratio can be about 6: 4 or about 8: 2.
Carrier compositions comprises the phosphate cpd of the electron transfer agent of following amount: preferably at about 0.01%w/w of carrier total concentration to about 20%w/w, more preferably about 0.01%w/w is to about 10%w/w, extremely about 5%w/w or about 0.01%w/w extremely in the scope of about 1%w/w of about 0.01%w/w most preferably.Carrier compositions can comprise the phosphate cpd of the electron transfer agent of following amount: in the scope of about 0.01%w/w to 2%w/w, and preferably about 0.05%w/w, about 0.1%w/w or about 1%w/w.In another embodiment, applicable about 5%w/w is to about 10%w/w or the about 10%w/w scope of about 15%w/w extremely.
Polar protic property solvent
Organic solvent can be categorized as nonpolar or polar aprotic solvent and polar protic property solvent.
Organic solvent of the present invention is a polar protic property solvent." protonic solvent " is the solvent with the hydrogen atom (respectively like hydroxyl or amino) that links to each other with oxygen atom or nitrogen-atoms.More at large, comprise and dissociated hydrionic any molecular solvent all can be considered to protonic solvent.On the contrary, " non-protonic solvent " can not provide hydrion.
Polar protic property solvent can be acyclic alcohol, Arrcostab, ketone or nitrile.Acyclic alcohol can be selected from C 1-C 4Acyclic alcohol (comprising its polyhydric alcohol), polymer and derivant thereof (for example ester, Arrcostab, ether).Some instances of these acyclic alcohol comprise ethanol, normal propyl alcohol, isopropyl alcohol, glycol (like propylene glycol, Polyethylene Glycol (like PEG400), diethylene glycol monoethyl ether) and ethyl acetate.Ketone can be selected from methyl iso-butyl ketone (MIBK) and acetone.Nitrile can be an acetonitrile.
Carrier compositions can only comprise a kind of polar protic property solvent; But, also can use the combination of polar protic property solvent.For fear of any query, it should be noted that the singulative to any characteristic used herein should be regarded as comprising plural form, offers some clarification on only if do in addition in the context.
Carrier compositions has high relatively polar protic property solvent strength.Polar protic property solvent strength preferably about 60%w/w to about 90%w/w, more preferably about 65%w/w extremely about 85%w/w, most preferably at about 70%w/w extremely in the scope of about 80%w/w.Polar protic property solvent strength can be about 70%w/w or about 80%w/w.In some cases, the OK range of polar protic property solvent strength can be about 50%w/w to about 60%w/w, and about 60%w/w is about 70%w/w or about 80%w/w about 90%w/w extremely extremely.
Bioactive compound
Term " bioactive compound " is meant any chemical substance with biological action that in the human or animal, is directed against medical science, treatment, beauty treatment or veterinary's purpose, and comprises the medicine of containing medicine, medicine woman's persona article (cosmeceutical), health nutrient (nutraceutical) and nutrient.Should be understood that some bioactive compound can be sorted in more than one these classifications.
Diversified bioactive compound can be sent with carrier compositions of the present invention.Preferably, said active bio chemical compound is lipophilic, and has low relatively molecular weight and low relatively fusing point.
Term " lipotropy " refers to chemical compound dissolved ability in fat, oil, lipid and non-polar solven (like hexane or toluene).The lipotropy of bioactive compound can be assessed through its octanol/water partition coefficient (logP value), and this partition coefficient is considered to proximate membrane permeability.
The permeable bioactive compound of percutaneous possibly have about 2.5 to about 3.5 logP value.The bioactive compound that bioactive compound and the logP value of the logP value that discovery is prepared with carrier compositions of the present invention in this scope (is higher or lower than) outside this scope is that percutaneous is permeable more, and promptly the logP value is at about 1 bioactive compound to about 5 the scope.Therefore, the logP value of bioactive compound can be about 1 to about 2.5 scope, about 2.5 to about 3.5 scope and about 3.5 to about 5 scope.
Do not hope bound by theory, believe that carrier compositions of the present invention can change one or more A.D.M.E. of bioactive compound (absorption, distribution, metabolism and drainage) characteristic, to improve sending of bioactive compound.Become effective bioactive compound, this bioactive compound not only must be effective to target body, and must have the A.D.M.E. characteristic of suitable necessity, uses so that it is suitable as bioactive compound.
" low relatively molecular weight " is meant less than about 1000 daltonian molecular weight, and preferably less than about 500 dalton, more preferably about 200 dalton are to about 300 daltonian scopes.
" low relatively fusing point " is meant and is lower than about 400 ℃ fusing point.
Diversified bioactive compound can be sent with carrier compositions of the present invention.Instance includes but are not limited to cardiovascular drug, particularly hypotensive agent (for example calcium channel blocker (or calcium antagonist)) and anti-arrhythmic; The congestive heart failure medicine; The muscle contraction medicine; Vasodilation; Angiotensin converting enzyme (ACE) inhibitor; Diuretic; Carbonic anhydrase inhibitors; Cardiac glycoside; Phosphodiesterase inhibitor; Alpha blocker; Beta-blocker; Sodium channel inhibitor; Potassium channel antagonists; The beta-adrenergic agonist; Platelet suppressant drug; The Angiotensin II antagonist; Anticoagulant; Thrombolytics; The treatments for bleeding thing; The treatment for anemia thing; Thrombin inhibitor; Antiparasitic; Antibacterial; Anti-inflammatory agent, particularly NSAID (NSAID), more particularly cox 2 inhibitor; The steroidal anti-inflammatory medicine; Preventative anti-inflammatory agent; Betimol; Mast cell stabilizers; Mydriatic; Influence the medicine of respiratory system; The allergic rhinitis medicine; The alpha-adrenergic agonist; Corticosteroid; The chronic obstructive pulmonary disease thing; Xanthine oxidase inhibitor; Anti-arthritic; Gout treatment thing medicine; Endocrine and endocrine antagonist; Anti-mycobacteria medicine; Antifungal agent; Antiprotozoal drug; Vermifuge; Special antiviral agent to respiratory tract, herpesvirus, cytomegalovirus, HIV and virus infection; The therapeutic agent of leukemia and Kaposi sarcoma; Pain therapy medicine, particularly anesthetis and analgesic, opioid drug comprises opioid receptor agonist, the local agonist of opiate receptor, opioid antagonist or opiate receptor mixing excitement-antagonist; Antipsychotic drug; Sympathomimetic; 2-adrenergic agonist components; The mediator that affects the nerves picked-up or the medicine that discharges; Anticholinergic; Antihemorrhoidal drug; The medicine of prevention or radiotherapy or chemotherapy effect; Produce fatty medicine (liopgenisis dtug); Fat reduces therapeutic agent; Appetrol such as lipase inhibitor; Sympathomimetic; Gastric ulcer and inflammation treatment agent are like proton pump inhibitor; Prostaglandin; The VEGF inhibitor; Blood lipid-lowering medicine, particularly Statins; Influence the medicine of central nervous system (CNS), like psychosis, antuepileptic and anticonvulsant, psychoactive drug, analeptic, antianxiety drugs and sleeping pill, antidepressants; The anti-Parkinson medicine; Hormone and fragment thereof are like gonadal hormone; Growth hormone antagonist; Gonadotropin releasing hormone and analog thereof; Steroid hormone and antagonist thereof; The selective estrogen regulator; Somatomedin; Antidiabetic drug is like blood sugar lowering; H1, H2, H3 and H4 antihistaminic; Be used to treat migrainous medicine; Asthma drug; Cholinergic antagonist; Glucocorticoid; Androgen; Androgen antagonist; The adrenocortical hormone biosynthesis inhibitor; The osteoporosis therapy agent is like bis phosphoric acid salt (biphosphonates); Antithyroid drug; Sunscreen cream, solar protection agent and lightscreening agent (filter); The cytokine agonist; Cytokine antagonist; Antineoplastic agent; Anti-senile dementia disease medicine; The HMGCoA reductase inhibitor; Shellfish special type (fibrates); Cholesterol absorption inhibitor; HDL cholesterol rising medicine; The triglyceride reducing medicine; Defying age or anti-wrinkle medicine; Antimicrobial drug; Anti-acne medicine (antiacne agent); Antioxidant; Hair treating agent and skin-whitening agents; Be used to treat or prevent the micromolecule curative of humans and animals disease, like allergy/asthma, arthritis, cancer, diabetes, retardation of growth, cardiovascular disease, inflammation, immune system obstacle, alopecia, pain, ophthalmic diseases, epilepsy, gynecological's obstacle, CNS disease, viral infection, bacterial infection, parasitic infection, gastrointestinal tract (G1) disease, obesity and BLOOD DISEASE.
The technical staff in field of the present invention can confirm whether certain particular organisms reactive compound is suitable for using with carrier compositions of the present invention.Some concrete limiting examples of suitable bioactive compound comprise:
Anesthetis:
Comprise amino-ester and amino-amide anesthetis, like benzocaine, chloroprocaine, ***e, reserpine, guanethidine, cyclomethycaine, dimethocaine/larocaine, propoxycaine, procaine/novocain, proparacaine, tetracaine/A Mei institute caine, articaine, bupivacaine, carticaine, cinchocaine/cinchocaine, etidocaine, chirocaine, lignocaine/lignocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, propofol, halothane, enflurane barbiturate, benzodiazepine
Figure BDA00001798709900091
type medicine, neostigmine and Ke Ta life.
Alkylating agent:
Comprise carmustine, cyclophosphamide, ifosfamide, streptozotocin and chlormethine.
Calcium channel blocker:
Comprise amlodipine; Aranidipine; Azelnidipine; Barnidipine; Benidipine; Cilnidipine; Clevidipine; Cronidipine; Darodipine; Dexniguldipine; Efonidipine; Elnadipine; Elgodipine; Felodipine; Flordipine; Furnidipine; Iganidipine; Isradipine; Lacidipine; Lemildipine; Lercanidipine; Manidipine; The beautiful Horizon (mesuldipine) that relaxes; Nicardipine; Nifedipine; Niludipine; Nilvadipine; Nimodipine; Nisoldipine; Nitrendipine; Olradipine; Oxodipine; Palonidipine; Pranidipine; Sagandipine; Sornidipine; Teludipine; Tiamdipine; Trombodipine; Irrigate his Horizon (watanidipine); Verapamil; Gallopamil; Benzothiazepine
Figure BDA00001798709900092
diltiazem
Figure BDA00001798709900093
mibefradil; The general ground of benzene that; Fluspirilene and fendiline.
Anti-arrhythmic and anti-anginal drug:
Comprise amiodarone, disopyramide, flecainide acetate, quinidine sulfate, nitroglycerin, ranolazine, amiodarone, isosorbide and alteplase.
Antimicrobial drug, antibiotic and anti-acne medicine
Comprise the amoxicillin; The phenalgin penicillin; Azithromycin; Benethamine penicillin; Bleomycin; Benzoyl peroxide; Cinoxacin; Chloromycetin; Daunomycin; Plicamycin; Fluoroquinolone; Ciprofloxacin; Clarithromycin; Clindamycin; Clindesse; Clofazimine; The gluconic acid chlorhexidine; Chlorine spills XiLin; Demeclocycline; Doxycycline; Erythromycin; Ethionamide; Imipenum; Indomethacin; Lymecycline; Minocycline; Nalidixan; Nitrofurantoin; Penicillin; Rifampicin; Spiramycin; Sulphacetamide; Sulfabenzamide; Sulfamethoxine; Sulfamethyldiazine; Sulfacetamide; Sulfadiazine; Sulfafurazole; Sulfamethoxazole; Sulfapyridine; Tetracycline; Cefalexin; Cefdinir; Triclosan; Ofloxacin; Vancoin; Glibenclamide (glyburide); Mupirocin; Cefprozil; CEFUROXIME AXETIL; Norfloxacin; Isoniazid; .beta.-bitter acid; Beracilline; Levofloxacin; Gatifloxacin and trimethoprim.
Anticarcinogen:
Comprise amycin, 6-thioguanine, paclitaxel, docetaxel, camptothecine, megestrol acetate, nvelbine (navelbine), cytosine arabinoside, fludarabine, Ismipur, 5-fluorouracil, teniposide, vinblastine, vincristine, cisplatin, colchicine, carboplatin, methylbenzyl hydrazine and etoposide.
Antidepressants, psychosis and antianxiety drugs:
Comprise alprazolam; Amoxapine; Bentazepam; Bromazepam; Chlorine ammonia
Figure BDA00001798709900101
(clorazipine); Clobazam; Clotiazepam; Diazepam; Lorazepam; Flunitrazepam; Flurazepam; Lormetazepam; Medazepam; Nitrazepam; Oxazepam; Temazepam; Maprotiline; Mianserin; Nortriptyline; Risperidone; Sertraline; Trazodone; Baloperidol; The stangyl fluoxetine; Ondansetron; Midazolam; Chlorpromazine; Haloperidol; Triazolam; Clozapine; Triflupromazine; Fluphenazine decanoate; Fluanisone; Perphenazine; Pimozide (pimozide); Prochlorperazine; Sulpiride; Mellaril; Paroxetine; Citalopram; BUP; Phenelzine; Olanzapine; Divalproex sodium and venlafaxine.
Opioid drug:
Comprise opioid receptor agonist and antagonist; Show and mix active chemical compound of agonist/antagonist and the chemical compound that shows partial agonist activity, comprise morphine, the general morphine of enlightening (depomorphine), etorphine, diacetylmorphine, hydromorphone, oxymorphone, levorphanol, methadone, levacetylmethadol (levomethadyl), Pethidine, fentanyl, sufentanil, alfentanil, codeine, hydrocodone, oxycodone, thebaine, desomorphine, nicomorphine, two propionyl morphines, benzyl morphine, ethylmorphine, Pethidine, methadone, tramadol, dextropropoxyphene, naloxone and naltrexone, buprenorphine, nalbuphine, butorphanol, pentazocine and ethyl ketone base cyclazocine (ethylketocyclazocine).
The tricyclic antidepressants medicine:
Comprise azathioprine, amitriptyline, famotidine, promethazine, paroxetine, oxcarbazepine (oxcarbazapine) and mirtazapine (mertazapine).
Antidiabetic drug:
Comprise acetohexamide (acetohexamide), chlorpropamide, glibenclamide (glibenclaraide), gliclazide, glipizide, metformin, tolazamide, glibenclamide, glimepiride and tolbutamide.
Antuepileptic:
Comprise beclamide, carbamazepine, gabapentin, tiagabine, vigabatrin (vigabatrin), topiramate, clonazepam, ethotoin, mephenytoin, mesuximide, mebaral, oxcarbazepine, paramethadione, phenacal, phenobarbital, phenytoin, phensuximide, primidone, easypro thiazine, phenytoin Sodium, cistofuran monohydrate, gabapentin, lamotrigine, zonisamide, ethosuximide and valproic acid.
Sleeping pill/tranquilizer and muscle relaxant
Comprise Zolpidemtar Trate, amobarbital, barbital, butobarbital, pentobarbital, brotizolam, carbromal, chlordiazepoxide, clomethiazole, methaqualone (methaqualome), miltown, methaqualone (methaqualome), the ring general woods of benzene (cyclobenzaprene), cyclobenzaprine, tizanidine, baclofen, butalbital, zopiclone, atracurium, tubocurarine and phenobarbital.
Antifungal agent, antiprotozoal drug and antiparasitic:
Comprise amphotericin, Nitric acid butoconazole, clotrimazole, econazole nitrate, fluconazol, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terconazole (triaconazole), tioconazole and undecylenic acid, benznidazole, clioquinol, deccox, diiodohydroxyquinoline, diloxanide, dinitolmide, furazolidone (fuzolidone), metronidazole, nimorazole, nitrofural, ornidazole, terbinafine, clotrimazole, chloroquine, mefloquine, itraconazole, pyrimethamine, praziquantel, quinacrine, mebendazole and tinidazole.
Antihypertensive and cardiac treatment medicine
Comprise that Candesartan, hydralazine, clonidine, triamterene, felodipine, gemfibrozil, fenofibrate, nifedipine (nifedical), prazosin, mecamylamine, doxazosin, dobutamine and Xi Lai are for former times ester (cilexetil).
Antimigraine:
Comprise agit, gynergen, methysergide maleate, Pizotifen Maleate (pizotifen maleate) and Sumatriptan Succinate.
Muscarine antagonist:
Comprise atropine, benzhexol, biperiden, second promazine (ethopropazine), hyoscyamine, mepenzolate bromide, oxibutynin, benzene difficult to understand former times bright (oxyphencylcimine) and tropicamide.
Antitumor agent (or immunosuppressant)
Comprise aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, procarbazine, citric acid tamoxifen, testolactone, tacrolimus, mercaptopurine and sirolimus.
Antiparkinsonism drug:
Comprise bromocriptine methanesulfonate, levodopa, tolcapone, ropinirole, bromocriptine, blood sugar lowering such as sulfonylurea, biguanides, Alpha-glucosidase inhibitor, thiazolidinediones, cabergoline, carbidopa and lisuride maleate (lysuride maleate).
Antithyroid drug:
Comprise carbimazole (carbimazole) and propylthiouracil.
Antiviral agents:
Comprise amantadine, auspicious for promise Wei (retinovir), GS-504, acyclovir, famciclovir, ribavirin, VX-478, indinavir (indinavirm), rimantadine (rimantadine) and efavirenz, penciclovir, ganciclovir, vidarabine, Abacavir, adefovirdipivoxil, A Punawei (apmrenavir), Delavirdine, Didanosine, stavudine, zalcitabine, zidovudine, En Fuwei ground and interferon.
The heart contraction medicine:
Comprise amrinone, milrinone, Digitoxin, digoxin, enoximone, Allocor and medigoxin.
Lipid regulating agent (hypo an d hyper lipidemic agents):
Comprise fenofibrate, clofibrate, probucol, according to Ezetimibe (ezetimibe) and Tuo Chepu (torcetrapib).
Anti-inflammatory agent:
Comprise U.S. former times health (meoxicam), triamcinolone acetonide, cromoglicic acid (cromolyn), nedocromil, hydroxychloroquine, montelukast, zileuton, bundle Rust and meloxicam.
Antihistaminic:
Comprise fexofenadine, chloral hydrate, hydroxyzine, promethazine, cetirizine, cimetidine, marezine (clyclizine), meclizine, dimenhydrinate, loratadine, nizatidine (nizatadine) and promethazine.
Antiulcerative:
Comprise omeprazole, lansoprazole, pantoprazole and ranitidine.
Diuretic:
Comprise hydrochlorothiazide, amiloride, acetazolamide, furosemide and torasemide.
NSAID：
Comprise aryl alkanoic acid subtribe, it comprises diclofenac, aceclofenac, acemetacin, chlorophenol acid, bromfenac, etodolac, indomethacin, indomethacin method Buddhist nun ester, nabumetone, oxametacin, proglumetacin, sulindac and tolmetin; 2-arylpropionic acid (Lip river fragrant type) subtribe comprises alminoprofen, Benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, miroprofen, naproxen, Ao Shapu piperazine, pirprofen, suprofen, his fluorine Bill (tarenflurbil) and tiaprofenic acid; And N-aryl-anthranilic acid (fragrant that acid) subtribe, comprise flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid; Trometamol, celecoxib, nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam, Phenylbutazone (pheylbutazone), tolmetin, indomethacin, acetaminophen (acetominophen) (acetaminophen), tramadol and third oxygen are fragrant.
The class xanthoplane:
Comprise first generation class xanthoplane, like retinol, retinal, retinoic acid (tretinoin, all-trans-retinoic acid), Accutane and A Li retinoic acid; Second filial generation class xanthoplane is like etretinate and metabolite Ah Qu Ting thereof; Third generation class xanthoplane is like tazarotene, shellfish Bimbisara fourth and adapalene
Hormone and steroid:
Comprise thyroliberin (ACTH); Vassopressin (vassopressin); Atrionatriuretic factor (ANF); Beclometasone; Cortisone; Scopolamine; Dopamine; Epinephrine; Catecholamines; Cholecystokinin; Citric acid Crow rice phenol; Danazol; Dexamethasone; Diethylstilbestrol (DES); Ethinylestradiol; Fludrocortisone; Finasteride; Follicle stimulating hormone; Gastrin; Hydroxyprogesterone; Leptin (leptin); Lutropin; Medroxyprogesterone acetate; Mestranol (mestranol); Quinestrol; Methyltestosterone; Nandrolone; Norethindrone (norethindrone); Norethindrone (norethisterone); Norgestrel; Estradiol; Put together estrogen; Oxandrolone; Oxytocin; Prednisone; Progesterone; Prolactin antagonist; Protogalndins; Somatostatin; Stanozolol; Diethylstilbestrol; Thyroxine; Prednisolone phosphate; Triamcinolone; The acetone mifepristone; Budesonide; Levothyroxine; Testosterone; Depo-testosterone; Fluoxymesterone; Flutamide; Momestasone furoate; Cyproterone; Fluorine Myron (fluromethalone); Goserelin; Leuprorelin; Calcitonin; Halogen Beta rope; Hydrocortisone and tibolone.
Statins and derivant:
Comprise atorvastatin, fluvastatin, lovastatin, nystatin, Rosuvastatin, pravastatin, orlistat and simvastatin.
Analeptic:
Comprise amphetamine, phentermine, tyramine, ephedrine, metaradrine, phyenlephrinium, dextroamphetamine, dexfenfluramine, fenfluramine, nicotine, caffeine and Mazindol.
Vasoconstrictor:
Comprise Desmopressin.
Vasodilation (vasodilitor):
Comprise carvedilol, terazosin, phentolamine and Mentholum.
The anti-Alzheimer disease medicine:
Comprise levetiracetam, levitiracetam and donepezil.
ACE inhibitor:
Comprise benazepril, enalapril, ramipril, fosinopril sodium, lisinopril, minoxidil, Soquad, rampril and quinapril.
The beta-2 adrenoceptor antagonist:
Comprise atenolol, timolol, pindolol, propranolol hydrochloride, bisoprolol, esmolol, metroprolol succinate, metoprolol and spectinomycin hydrochloride.
The Angiotensin II antagonist:
Comprise losartan.
Platelet suppressant drug:
Comprise abciximab, clopidogrel, tirofiban and aspirin.
Alcohols and phenols:
Comprise tramadol, tramadol hydrochloride, allopurinol, calcitriol, cilostazol, sotalol, Coflodiol (urasodiol), bromperidol, droperidol, Flupentixol Decanoate, albuterol, salbutamol sulfate, carisoprodol, clobetasol, ropinirole, labetalol and methocarbamol.
Ketone and esters:
Comprise amiodarone, fluticasone, spironolactone, prednisone, trazodone, desoximetasone, methyl prednisone, benzonatate, nabumetone and buspirone.
Bendectin:
Comprise metoclopramide.
The eye therapeutic agent:
Comprise dorzolamide, brimonidine, olopatadine, cyclopentolate, pilocarpine and echothiophate.
Anticoagulant and antithrombotic agents:
Comprise warfarin, Enoxaparin (enoxaparin) and lepirudin.
The gout treatment agent:
Comprise probenecid and sulfinpyrazone (sulfinpyrazone).
COPD and treating asthma agent:
Comprise ipratropium bromide (ipratropium).
The osteoporosis therapy agent:
Comprise raloxifene, pamldronate and Risedronate.
Preferred especially bioactive compound comprises lignocaine, diclofenac, ketorolac, prilocaine, halogen doubly his rope, hydrocortisone and combination thereof.
The pharmaceutically acceptable derivant that should understand bioactive compound within the scope of the present invention.
Term " pharmaceutically acceptable derivant " includes but are not limited to salt, the ether of pharmaceutically useful salt, ester, these esters or comprises prodrug and any other derivant of metabolite; When needed object is used, said derivant can provide the bioactive compound described in this paper directly or indirectly.
The term that uses among this paper " officinal salt " is meant in the scope that rational medicine is judged, be applicable to contact with people or zootic tissue and do not have excessive toxicity, zest, an anaphylaxis etc., and with rational benefit/risk than those salt that match.Officinal salt is well known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences, and 66:1-19 describes officinal salt in detail in 1977.The instance of pharmaceutically useful non-toxic acid addition salts is the amino salt that forms with mineral acid or organic acid; Said mineral acid for example is hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid; Said organic acid for example is acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or the salt through utilizing the additive method (for example ion exchange) that uses in this area to form.Other officinal salt comprises adipate; Alginate; Ascorbate; Aspartate; Benzene sulfonate; Benzoate; Disulfate; Borate; Butyrate; Camphorate (camphorate); Camsilate; Citrate; Cyclopentane propionate; Digluconate; Lauryl sulfate; Esilate; Formates; Fumarate; Gluceptate; Glycerophosphate; Gluconate; Hemisulphate (hernisulfate); Enanthate; Caproate; Hydriodate; 2-hydroxyl-esilate; Lactobionate; Lactate; Laruate; Lauryl sulfate; Malate; Maleate; Malonate; Mesylate; The 2-naphthalene sulfonate; Nicotinate; Nitrate; Oleate; Oxalates; Palmitate; Palmoxiric acid salt; Pectate (pectinate); Persulfate; 3-phenylpropionic acid salt; Phosphate; Picrate; Pivalate; Propionate; Stearate; Succinate; Sulfate; Tartrate; Rhodanate; Tosilate; The hendecane hydrochlorate; Valerate etc.Representational alkali metal salt or alkali salt comprise sodium, lithium, potassium, calcium, magnesium etc.Other officinal salt also comprises the amine cation that nontoxic ammonium salt, quaternary ammonium salt and use counter ion counterionsl gegenions (like halogen ion, hydroxyl, carboxylate radical, sulfate radical, phosphate radical, nitrate anion, low alkyl group sulfonate radical and aryl sulfonic acid root) form in the time of suitably.
Term " pharmaceutically acceptable ester " is meant the esters of hydrolysis in vivo, and comprises easy those esters that stay parent compound or its salt that in human body, decompose.Suitable ester group for example comprises those ester groups, particularly alkanoic acid, alkenoic acid, aphthenic acids and the chain docosandioic acid derived from pharmaceutically acceptable aliphatic carboxylic acid, and wherein each alkyl or alkenyl part advantageously has no more than 6 carbon atoms.The instance of concrete ester comprises formic acid esters, acetate, propionic ester, butyrate, acrylic ester and ethyl succinate.
Term used herein " pharmaceutically acceptable prodrug " refers to those prodrugs of bioactive compound; In the scope that rational medicine is judged; It is suitable for contacting with the tissue of object and does not have excessive toxicity, zest, anaphylaxis etc.; Match with rational benefit/risk ratio, and can be effective to its desired use, also can comprise the zwitterionic form of The compounds of this invention.Term " prodrug " is meant the chemical compound that transforms the parent compound that discharges top molecular formula in vivo rapidly, for example through hydrolysis in blood.T.Higuchi and V.Stella; Pro-drugs as Novel Delivery Systems; A.C.S.Symposium Series the 14th volume, and Edward B.Roche compiles Bioreversible Carriers in Drug Design; American Pharmaceutical Association and Pergamon Press provides deep discussion in 1987.
Bioactive compound can exist with the amount up to about 30%w/w of carrier compositions total concentration.Preferably, the amount of bioactive compound is up to about 10%w/w, more preferably up to about 6%w/w, most preferably at about 0.1%w/w to the scope of about 5%w/w.
Carrier compositions improves sending of bioactive compound through the A.D.M.E. performance that changes bioactive compound.Do not hope bound by theory; Believe because the phosphate cpd of electron transfer agent has changed the dissolubility of bioactive compound in different barriers (skin, mucosa, muscle etc.) with the combination of the polar protic property solvent of relative high concentration, so changed the A.D.M.E. characteristic of bioactive compound.This time of staying of dissolubility variable effect medicine in these tissues, and postpone or shorten medicine to get into the time of eliminating phase.Therefore, carrier compositions of the present invention can provide following advantage:
-reduction side effect (for example reducing undesired systemic effect);
-restriction bioactive compound is distributed to specific region (like drug targeting);
-improve patient's compliance (for example consumption is still less used still less);
-improve outward appearance (for example rapid draing); And
-increase acting duration and/or shorten onset time.
Carrier compositions of the present invention can also improve the bioavailability of bioactive compound in object.
The present invention can also be used in the method for disease of treatment target, and said method comprises the bioactive compound that is applied in the effective dose in the carrier compositions of the present invention.Said disease comprises those diseases that can treat through the bioactive compound of preparing with said carrier compositions.
What the term that uses among this paper " object " referred to have symptom relevant with disease or that caused by disease need be with any animal of bioactive compound treatment.Said animal can be a mammal, and preferred people perhaps can be inhuman primate or non-human primate animal, for example in animal model test, uses.Especially, be applicable to people's Drug therapy although estimate preparation of the present invention, it also is applicable to beastly disease treatment, comprises treatment companion animals (for example Canis familiaris L. and cat); And domestic animal (for example horse, pony, donkey, mule, yamma, alpaca, pig, cattle and sheep); Or zoo animal (for example primate, felid, Canis animals, bovid and ungulate.
Usually, the term that uses among this paper " treatment " means influences object, tissue or cell to obtain the pharmacology and/or the physiologic effect of expectation.Said effect can be in the prophylactic effects of preventing wholly or in part aspect a kind of or more kinds of pathological condition, and/or can be in the therapeutic effect of partially or completely curing aspect a kind of or more kinds of pathological condition.
Route of administration
Route of administration can be divided into three kinds of strategies roughly according to effect, i.e. " surface " (" topical "), and its desired effects is partial, so material is applied directly to its desired working place; " enteral ", its desired effects are whole body (non-local), so material provides through digestive tract; And " parenteral ", its desired effects is a whole body, so material provides through the approach except that digestive tract.
111 kinds of different route of administration are admitted by food and drug administration.It below is the non-limiting inventory of the instance of route of administration.
Instance with surface applied approach of partial result comprises in epidermis (to skin) and the vitreous body (to eyes).
Instance with enteral route of administration of whole body (non local) effect comprises any administration form that relates to the gastrointestinal tract any part, for example oral (in mouth), intranasal (to intranasal), rectum (to internal rectum) and vagina (to intravaginal).
Through injection; The instance of the parenteral administration approach with whole body effect of infusion or diffusion comprises intravenous (to intravenous); Intra-arterial (to intra-arterial); Intramuscular (in muscle); In the heart (in heart); Subcutaneous (under skin); Percutaneous (through pin-be punctured in the skin); Intradermal (in skin self); In the capsule (in canalis spinalis); Intraperitoneal (infusion or be expelled to intraperitoneal); Intravesical infusion (being infused into intravesical); In the dura mater (inject or be infused in the epidural space); Transdermal (through the intact skin diffusion); Pass through mucosa (through the mucosa diffusion); Insufflation (through the nose diffusion); Suck (through port diffusion); Sublingual (Sublingual); And suck (absorbing) through near the buccal gingiva.
According to preparation of the present invention can be that any suitable administration form is (for example, referring to Pharmaceutics and Pharmacy Practice, J.B.Lippincott Company; Philadelphia; Pa., Banker and Chalmers compile, 238-250 page or leaf (1982)).The instance of suitable administration form includes but are not limited to solution, liquid, suspension, gel, poultice (poultice), reservoir devices patch (reservoir patch) and emulsifiable paste.Preparation can be sent with a kind of prepare and storage and with another kind of form, and for example, preparation can store and send with form of foam with liquid form.Preparation can be prepared by any method that pharmaceutical field is known, like RemingtonJ.P., and The Science and Practice of Pharmacy; A.R.Gennaro compiles, and the 20th edition, Lippincott; Described in the Williams and Wilkins Baltimore, Md. (2000).These methods comprise bioactive compound and carrier combinations, make preparation be configured as the step of desired product (if desired) then.
The preparation carrier compositions
Carrier compositions of the present invention can be prepared by multiple technologies.
A method of preparation carrier compositions comprises the combination of components with an amount of carrier compositions, stirs, until reaching complete homogenize.
In a method for optimizing, with the phosphate cpd and the polar protic property solvent combinations of electron transfer agent, and warm down at 40 ℃ until forming solution.Water (smaller size smaller usually) is heated to 40 ℃, is added drop-wise to then in the said solution and forms carrier compositions.Perhaps, can the phosphate cpd and the polar protic property solvent combinations of electron transfer agent be added drop-wise to said aqueous phase in some cases.The final pH that can regulate carrier compositions is to improve stability, for example through adding sodium hydroxide.Usually, carrier compositions is clarification to a transparent solution.
According to the dissolubility and the stability of bioactive compound, can with its be soluble in the aqueous phase or solvent phase in.
Said carrier compositions also can be chosen wantonly and comprise a kind of or more kinds of excipient.It will be apparent to those skilled in the art that the suitable excipient that can be included in carrier compositions of the present invention or the preparation.The selection of other excipient will be depended on the characteristic of bioactive compound and used administration form.The instance of other excipient comprises other solvent, for example water, thickening agent or gellant, surfactant, buffer, demulcent (emollient), sweeting agent, disintegrating agent, flavouring agent (flavour), coloring agent, aromatic (fragrance), electrolyte, outward appearance modifying agent, thin film foamable polymer, propellant etc.Suitable disintegrants comprises corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable gellant comprises hydroxypropyl cellulose (HPC) and carbopol.Suitable flavouring agent comprises Oleum menthae, wintergreen oil, Fructus Pruni pseudocerasi, Fructus Citri tangerinae or Fructus Rubi spice.Suitable propellant comprises butane, carbon dioxide, ethane, hydrogen fluorochlorohydrocarbon, iso-butane, nitrogen, nitric oxide, propane, dimethyl ether, isoamyl alcohol, pentane and composition thereof, for example propellant A-46 (20% propane and 80% iso-butane).The organic solvent of high concentration can avoid further adding the needs of antiseptic relatively; But if think in case of necessity, addible suitable preservatives comprises sodium benzoate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and sodium sulfite.
The amount of a kind of or more kinds of excipient (if exist) is preferably the about 10%w/w up to the carrier compositions total concentration, more preferably up to about 5%w/w, and most preferably up to about 3%w/w, even more preferably 0.01-3%w/w or 0.1-1%w/w.
Find that carrier compositions of the present invention and preparation are stable on the physiology, do not have particle diameter greater than 300nm.There is not spontaneous sol-gel to transform yet.
Description of drawings
With reference to following accompanying drawing instance is described, wherein:
Fig. 1 show the preparation comprise oxycodone external at the Forlan transdermal delivery in pond (Franz cell) now;
Fig. 2 A and 2B show the relative behavior of preparation in dose response that comprises oxycodone;
Fig. 3 shows the relative skin deposits result of the preparation that comprises lignocaine;
Fig. 4 shows the relative skin deposits result of the preparation that comprises diclofenac; And
Fig. 5 shows the relative skin deposits result of the preparation that comprises ketorolac.
Embodiment
To describe multiple embodiments/aspect of the present invention with reference to following non-limiting example now.
Embodiment 1
Prepared carrier compositions according to above-described method for optimizing.
Each of five kinds of carrier compositions all comprises list-(fertility phenolic group) phosphate ester and two-(fertility phenolic group) phosphate mixture (ratio is 8: 2) and water of 1%w/w, and has following polar protic property solvent strength:
% polar protic property solvent
?(i) 50%w/v ethanol
?(ii) 60%w/v ethanol
?(iii) 70%w/v ethanol
?(iv) 80%w/v ethanol
?(v) 90%w/v ethanol
Thermal cycling method
About 12 hours of about 5 ℃ of following cold preservations, it was passed through about 12 hours under about 30 ℃ temperature carrier compositions, carry out 3 circulations.During each change temperature, any muddiness and deposition were at room temperature placed 3 hours and observed to carrier compositions.
Clarity of solution Precipitate
?(i) Slight haze Do not have
?(ii) Clarification Do not have
?(iii) Clarification Do not have
?(iv) Clarification Do not have
?(v) Clarification Do not have
Embodiment 2
Present embodiment has compared with preparation of the present invention (preparation 2A) and the preparation (preparation 2B) that comprises the polar protic property solvent of low concentration at external oxycodone dermal delivery.The details of each preparation is following:
Figure BDA00001798709900211
Figure BDA00001798709900212
The pH of preparation 2A is 6.The pH of preparation 2B is 6.4.
Method
Prepared preparation 2A according to above-mentioned method for optimizing.Prepared preparation 2B similarly.
The vertical Forlan of 12ml now diffusion cell (PermeGear uses the rat abdomen skin of through thickness in PA).With rat through using CO 2Gas suffocates and puts to death and abdomen area is shaved hair carefully also cut.Remove all subcutaneous fats and connective tissue.Skin is being frozen flat and is being stored under-20 ℃ until testing morning on the same day between the tinfoil paper scraps of paper.
Now use in the pond PBS as receptor solution (12ml) at Forlan, and Forlan have the surface area of 1.77cm2 in the pond now.Experimental session maintains 32 ℃ with said pond.Use limiting dose (40 μ l) to be similar to the condition of using in the body.Regularly the sampling receptor solution is 4 hours, analyzes with the percutaneous absorption of mensuration oxycodone and with HPLC.The result is presented among Fig. 1.Said result is the meansigma methods of n=8-10 diffusion cell of statistics separately through two days.The bar line is represented SEM.
The result
Find that preparation 2A (having 70%w/w polar protic property solvent strength) can keep the oxycodone concentration of 5%w/w.On the other hand, preparation 2B (having 20%w/w polar protic property solvent strength) only can keep the oxycodone concentration of maximum 1.5%w/w.
Although two kinds of preparations all can the transdermal delivery oxycodone, the result shows, after 4 hours, sends about 18 μ g oxycodones with preparation 2B and compares, and preparation 2A sends about 130 μ g oxycodones.
Except total amount increases, also cause delivery rate (being flux) fast the drying time of preparation 2A.For preparation 2A, the linear flux (J) that the oxycodone percutaneous absorbs is 40 μ gh/cm 2, preparation 2B then has 5.54 μ gh/cm 2Flux.
The two all can be partly owing to the oxycodone concentration (and dosage subsequently) that increases although the oxycodone that increases is sent flux and amount, and the result shows that preparation 2A also has high bioavailability.Preparation 2A discharges oxycodone from total application dosage percent is about 8%, and by contrast, preparation 2B then is merely about 3%.
Conclusion
With respect to preparation 2B, preparation of the present invention (preparation 2A) can increase oxycodone concentration.Also this shows better oxycodone percutaneous aspect two and absorbs preparation 2A in oxycodone delivery rate and total amount, and superior bioavailability.
Embodiment 3
Present embodiment is dose response research, and it has compared the performance of preparation of the present invention (preparation 3A) and aqueous compositions (preparation 3B), to confirm its relative behavior in dose response.The details of every kind of preparation is following:
Figure BDA00001798709900231
Figure BDA00001798709900232
The pH of preparation 3A is 6.The pH of preparation 3B is 8.
Method
Prepared preparation 3A according to above-mentioned method for optimizing.Prepared preparation 3B similarly.
The vertical Forlan of 12ml now diffusion cell (PermeGear uses the rat abdomen skin of through thickness in PA).With rat through using CO 2Gas suffocates and puts to death and abdomen area is shaved hair carefully also cut.Remove all subcutaneous fats and connective tissue.Skin is being frozen flat and is being stored under-20 ℃ until testing morning on the same day between the tinfoil paper scraps of paper.
Now use PBS as receptor solution (12ml) in the pond at Forlan, and Forlan have 1.77cm in the pond now 2Surface area.Experimental session maintains 32 ℃ with said pond.Use the condition of limiting dose (20-60 μ l) to use in the analogue body.Regularly the sampling receptor solution is 4 hours, analyzes with the percutaneous absorption of mensuration oxycodone and with HPLC.The gained result is in Fig. 2 A and 2B.
The result
Preparation 3A has the percutaneous flux of increase than preparation 3B.Use the feasible oxycodone (alkali that can prepare the preferred form of equivalent of polar protic property solvent (preparation 3A) of high concentration; 5%w/w).
Use 10-20 μ l/cm 2Equivalent dosage, preparation 3A has sent the oxycodone more than the twice of preparation 3B, two kinds of preparations all show good dose response.At 30 μ l/cm 2Dosage under, do not observe the further increase of dermal delivery among the preparation 3B.Even at 30 μ l/cm 2Maximum dose level under, the dose response of preparation 3A still continues.
Conclusion
The research of this dose response shows that especially preparation of the present invention (preparation 3A) allows the dose response of wideer dynamic range.
Embodiment 4
Present embodiment has compared preparation of the present invention (preparation 4A) and the stability, skin deposits and other characteristics that comprise the polar protic property solvent formulation (preparation 4B) of low concentration.The details of every kind of preparation is following:
Figure BDA00001798709900241
Figure BDA00001798709900242
Figure BDA00001798709900251
Method
Prepared preparation 4A according to above-mentioned method for optimizing.Prepared preparation 4B similarly.
The result
The vision stability test is the result show, stores after 3 days, observes that preparation 4A does not have physical change and preparation 4B has formed precipitate.
After using 4 hours, 4B compares with preparation, and preparation 4A has tangible skin deposits (μ g), and is as shown in Figure 3.
Conclusion
The result shows that 4B compares with preparation, and preparation of the present invention (preparation 4A) is stable and has improved and sent.
Embodiment 5
Present embodiment has compared preparation of the present invention (preparation 5A) and the stability of formulation, skin deposits and other characteristics that comprise the polar protic property solvent (preparation 5B) of low concentration.The details of every kind of preparation is following:
Figure BDA00001798709900261
Method
Prepared diclofenac formulations 5A according to above-mentioned method for optimizing.Prepared preparation 5B similarly.
The result
The vision stability test is the result show, stores after 3 days, observes that preparation 5A does not have physical change and preparation 5B has formed precipitate.
After using 4 hours, 5B compares with preparation, and preparation 5A has tangible skin deposits (μ g), and is as shown in Figure 4.In Fig. 4, also preparation 5A and 5B and the commercially available prod diclofenac
Figure BDA00001798709900262
that comprises diclofenac are compared.
Conclusion
The result shows that 5B compares with preparation, and preparation of the present invention (preparation 5A) is stable and has improved and sent.
Embodiment 6
Present embodiment has compared preparation of the present invention (preparation 6A) and stability of formulation, dermal osmosis and other its characteristics of comprising the polar protic property solvent (preparation 6B) of low concentration.The details of every kind of preparation is following:
Figure BDA00001798709900263
Figure BDA00001798709900271
Figure BDA00001798709900272
Method
Prepared preparation 6A according to above-mentioned method for optimizing.Prepared preparation 6B similarly.
Also to said preparation carried out with embodiment 2 in the similar dermal osmosis test carried out.
The result
The vision stability test is the result show, stores after 3 days, observes that preparation 6A does not have physical change and preparation 6B has formed precipitate.
After using 4 hours, 6B compares with preparation, and preparation 6A has tangible skin deposits (μ g), and is as shown in Figure 5.
Conclusion
The result shows that 6B compares with preparation, and preparation of the present invention (preparation 6A) is stable and has improved and sent.
Embodiment 7
Present embodiment has compared preparation of the present invention (preparation 7A) and has comprised the stability of formulation and other characteristics of the polar protic property solvent (preparation 7B) of low concentration.The details of every kind of preparation is following:
Figure BDA00001798709900281
Figure BDA00001798709900282
Method
Prepared preparation 7A according to above-mentioned method for optimizing.Prepared preparation 7B similarly.
The result
The vision stability test is the result show, stores after 3 days, observes that preparation 7A does not have physical change and preparation 7B has formed precipitate.
After using 4 hours, 7B compares with preparation, and preparation 7A has tangible skin deposits (μ g), shown in Fig. 7 B.
Conclusion
The result shows that 7B compares with preparation, and preparation of the present invention (preparation 7A) is stable and has improved and sent.
It will be understood by those skilled in the art that under situation without departing from the spirit and scope of the present invention, can make multiple modification the present invention.

Claims (21)

1. carrier compositions that is used for delivery of bioactive compounds, it comprises the phosphate cpd and the polar protic property solvent of electron transfer agent, and the concentration of wherein said polar protic property solvent is higher than the 50%w/w of said carrier compositions total concentration.
2. the carrier compositions of claim 1; The concentration of wherein said polar protic property solvent at about 60%w/w to about 90%w/w; Or about 65%w/w is to about 85%w/w, or about 70%w/w about 80%w/w extremely, or about 50%w/w about 60%w/w extremely; Or about 60%w/w is to about 70%w/w, or about 80%w/w is extremely in the scope of about 90%w/w.
3. the carrier compositions of claim 1, wherein said polar protic property solvent is an acyclic alcohol.
4. the carrier compositions of claim 3, wherein said C 2-C 3Acyclic alcohol is ethanol or propanol.
5. the carrier compositions of claim 1, wherein said electron transfer agent is a hydroxychroman.
6. the carrier compositions of claim 5, wherein said hydroxychroman is tocopherol or tocotrienol.
7. the carrier compositions of claim 6, the phosphate cpd of wherein said tocopherol is selected from list-(fertility phenolic group) phosphate ester, list-(fertility phenolic group) phosphate ester list sodium salt, list-(fertility phenolic group) phosphate ester monopotassium salt, list-(fertility phenolic group) organic phosphate disodium salt, list-(fertility phenolic group) phosphate ester di-potassium, two-(fertility phenolic group) phosphate ester, two-(fertility phenolic group) phosphate ester list sodium salt, two-(fertility phenolic group) phosphate ester monopotassium salt or its mixture.
8. the carrier compositions of claim 7, the phosphate cpd of wherein said tocopherol is the mixture of list-(fertility phenolic group) phosphate ester and two-(fertility phenolic group) phosphate ester.
9. the carrier compositions of claim 8, the ratio of list-(fertility phenolic group) phosphate ester and two-(fertility phenolic group) phosphate ester is at least 2: 1 in the wherein said mixture, perhaps about 4: 1 to about 1: 4 scope, perhaps at about 6: 4 to about 8: 2 scope.
10. the carrier compositions of claim 1; The amount of the phosphate cpd of wherein said electron transfer agent is that about 0.01%w/w of said carrier compositions total concentration is to about 20%w/w or about 0.01%w/w to about 10%w/w or about 0.01%w/w about 5%w/w or about 0.01%w/w extremely about 10%w/w or about 10%w/w extremely in the scope of about 15%w/w of about 2%w/w or about 5%w/w extremely extremely; Perhaps about 0.05%w/w; Perhaps about 0.1%w/w, perhaps about 1%w/w.
11. the phosphate cpd of electron transfer agent and the polar protic property solvent purposes in making carrier compositions, the concentration of wherein said polar protic property solvent is higher than the 50%w/w of said carrier compositions total concentration.
12. a method for preparing the carrier compositions of claim 1 comprises the phosphate cpd of said electron transfer agent and said polar protic property solvent combinations until the step that reaches complete homogenize.
13. one kind comprises the carrier compositions of claim 1 and the preparation of bioactive compound.
14. the preparation of claim 13, wherein said bioactive compound is lipophilic, its logP value about 1 to about 5 scope.
15. the preparation of claim 13, wherein said bioactive compound have low relatively molecular weight and/or low relatively fusing point.
16. the preparation of claim 13, wherein said bioactive compound exists with the amount up to about 30%w/w of said carrier compositions total concentration.
17. the preparation of claim 14, wherein said bioactive compound are selected from lignocaine, diclofenac, ketorolac, prilocaine, halogen doubly his rope, hydrocortisone and combination thereof.
18. the preparation of claim 17, wherein said bioactive compound exists with the amount up to the 5%w/w of said carrier compositions total concentration.
19. a method for preparing the preparation of claim 15 comprises the step of bioactive compound being added to the carrier compositions of claim 1.
20. the carrier compositions of claim 1 is used for improving sending of the bioactive compound prepared with said carrier compositions or is used to change the A.D.M.E. characteristic of bioactive compound or is used to improve the purposes of bioactive compound in the bioavailability of object.
21. the method for the disease of a treatment target comprises the bioactive compound that will treat said disease from effective dose to the object that these needs are arranged that use, wherein said bioactive compound is formulated in the carrier compositions of claim 1.
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